Department of Obstetrics & Gynecology, Wayne State University School of Medicine, 275 E. Hancock, Detroit, MI, 48201, USA.
Center for Molecular Medicine & Genetics, Wayne State University School of Medicine, 275 E. Hancock, Detroit, MI, 48201, USA.
Epigenetics Chromatin. 2023 Jan 24;16(1):3. doi: 10.1186/s13072-022-00475-2.
Preconception exposure to phthalates such as the anti-androgenic dibutyl-phthalate (DBP) impacts both male and female reproduction, yet how this occurs largely remains unknown. Previously we defined a series of RNAs expressly provided by sperm at fertilization and separately, and in parallel, those that responded to high DBP exposure. Utilizing both populations of RNAs, we now begin to unravel the impact of high-DBP exposure on those RNAs specifically delivered by the father.
Enrichment of RNAs altered by DBP exposure within the Molecular Signature Database highlighted cellular stress, cell cycle, apoptosis, DNA damage response, and gene regulation pathways. Overlap within each of these five pathways identified those RNAs that were specifically (≥ fivefold enriched) or primarily (≥ twofold enriched) provided as part of the paternal contribution compared to the oocyte at fertilization. Key RNAs consistently altered by DBP, including CAMTA2 and PSME4, were delivered by sperm reflective of these pathways. The majority (64/103) of overlapping enriched gene sets were related to gene regulation. Many of these RNAs (45 RNAs) corresponded to key interconnected CRREWs (Chromatin remodeler cofactors, RNA interactors, Readers, Erasers, and Writers). Modeling suggests that CUL2, PHF10, and SMARCC1 may coordinate and mechanistically modulate the phthalate response.
Mediated through a CRREW regulatory network, the cell responded to exposure presenting stressed-induced changes in the cell cycle-DNA damage-apoptosis. Interestingly, the majority of these DBP-responsive epigenetic mediators' direct acetylation or deacetylation, impacting the sperm's cargo delivered at fertilization and that of the embryo.
抗雄激素邻苯二甲酸二丁酯（DBP）等邻苯二甲酸酯在受孕前的暴露会影响男性和女性的生殖能力，但这是如何发生的还很大程度上不清楚。之前，我们定义了一系列精子在受精时专门提供的 RNA，并且单独地、平行地定义了那些对高 DBP 暴露有反应的 RNA。利用这两种 RNA 群体，我们现在开始揭示高 DBP 暴露对那些专门由父亲提供的 RNA 的影响。
在分子特征数据库中，受 DBP 暴露改变的 RNA 的富集突出了细胞应激、细胞周期、细胞凋亡、DNA 损伤反应和基因调控途径。在这五个途径中的每一个中都有重叠，确定了那些特别（≥五倍富集）或主要（≥两倍富集）作为父本贡献的一部分提供的 RNA，与受精时的卵子相比。受 DBP 一致改变的关键 RNA，包括 CAMTA2 和 PSME4，由反映这些途径的精子提供。重叠的富集基因集的大多数（64/103）与基因调控有关。这些 RNA 中的许多（45 个 RNA）对应于关键的相互连接的 CRREWs（染色质重塑因子共因子、RNA 相互作用体、读取器、擦除器和写入器）。建模表明，CUL2、PHF10 和 SMARCC1 可能协调并在机制上调节邻苯二甲酸酯的反应。
通过 CRREW 调控网络介导，细胞对暴露做出反应，表现出细胞周期-DNA 损伤-细胞凋亡的应激诱导变化。有趣的是，这些 DBP 反应性表观遗传介质的大多数直接乙酰化或去乙酰化，影响精子在受精时的携带物和胚胎的携带物。
